The following blog is an adaptation of a conference presentation by Covance in September 2020 that was also re-recorded and availablehere
Background: Medical monitoring supports the correct determination of patient eligibility for CAR T-cell therapy and plays a key role in monitoring quality patient care throughout CAR T clinical trials (see Figure 1 below). The COVID-19 pandemic presents multiple additional challenges to the safe conduct of medical monitoring in these types of trials:
- Transportation issues – impacts both patients and staff, whilst also disrupting cellular therapy products/technical resources shipments to and from labs and hospitals
- 工作人员短缺 - 由于Covid-19暴露或护理/医务人员被重定向到专家Covid-19单位
- Clinical resource shortages – PPE, mechanical ventilation and hospital beds may be reallocated to the crisis
图1。医学监测在整个汽车T细胞疗法中发挥作用
新指南from the CAR T-cell Consortium present an aligned approach to addressing these challenges to deliver optimum care for patients on CAR T therapy and in CAR T therapy clinical trials.1
Should CAR T treatments continue during the COVID-19 pandemic?
CAR T-cell therapies have provided unprecedented durable responses in patients with previously dismal prognoses. For most of these patients, delaying treatment is not a realistic option, due to otherwise dismal prognosis and the fife saving option represented by CAR T-cell therapies. Healthcare providers need to expertly triage patients who are most in need of urgent treatment – other noncellular therapies are unlikely to result in a durable response and are still associated with significant adverse events.
What considerations need to be made to safely administer CAR T-cell therapy during COVID-19?
Recommendations aim to limit direct patient contact and reduce risk to patients when they at their most immunodeficient. Treatments like lymphodepleting chemotherapy should begin only after the receipt of cell products, with patient housing support provided for at least 4 weeks after the procedure to spare travel needs, particularly during the pandemic. Where possible visitors should be restricted, and early interventions used to limit CRS (cytokine release syndrome)/neurotoxicity and prevent infection. Recommendations also call for telemedicine, reduced non-essential lab work/radiology appointments, oral medications over parenteral and outpatient rather than inpatient visits where appropriate.
Do recommendations for CAR T clinical trials differ depending on trial phase or context?
Although individual patient treatment lies with the treating physician, guidelines around continuing clinical trials aim to optimise use of resources, without compromising patient care. Recommendations therefore depend on specific patients, phase and context:
- 阶段i试验 - 原则上应限制或搁置，因为它们主要旨在展示安全
- Phase II trials – should be continued, as these could offer long-term benefit and possibility of cure
- Phase III trials or first-line therapy trials – should be placed on hold, as benefit is yet unproven vs. the standard of care
Enrolment should continue in trials aimed to test novel CRS and neurotoxicity prevention strategies, which might offer life-saving treatment whilst potentially minimizing toxicities and use of resources (such astocilizumab，在大流行期间可以改变哪些可用性）。
Overall CAR T-cell therapy should only be continued at expert treatment centers on optimal therapeutic candidates.
您如何在Covid-19期间接近选择NHL或所有患者进行汽车T细胞疗法？
对于成人复发/难治性/难治性（R / R）腐蚀性B细胞非霍奇金的淋巴瘤（B-NHL）治疗延续是患者类型的患者。指南建议推迟患者在高风险的汽车T细胞疗法失败，如快速肿瘤生长的替代品所示：LDH和绩效状况升高（ECOG> 2）。仅在汽车T后，单独服用的高龄未与较差的结果相关联，因此治疗应在65年超过65岁的患者中继续进行治疗。除此之外，应在r / r侵略性B-NHL患者中以2个或更多的以前的产品，根据标签，在R / R侵袭性B-NHL患者中提供汽车T细胞疗法。
For patients with R/R B cell acute lymphoblastic leukemia (B-ALL) up to 25 years, CAR T-cell therapy is lifesaving, and treatment should proceed. Overall ICU admission has also been lower since therapy approval, likely due to improved management of toxicities like CRS, further supporting the use of CAR T in these patients.
As this is largely a pediatric group the treatment considerations are slightly different:
- ICU bed availability may be an issue, especially for 18-25 age group in adult centers – transferring these patients to a pediatric center with more resources may be an option
- Tocilizumab availability –tocilizumab可能被重定向用于COVID-19患者therefore shortage could occur and availability should be confirmed upfront
- 一般床可用性大多不受儿科的影响，然而，由于感染或分配对Covid单位而可能存在儿科员工的不足
Covid-19如何测试适合汽车T细胞疗法治疗途径？
患者应在初始评估中进行Covid-19和24-72小时进行测试，然后预定开始淋巴射出化疗。如果RT-PCR测试回来阳性，则应延迟汽车T细胞程序，直至患者无症状，并且至少有两个连续的阴性PCR测试，一周分开。
Usual quarantine procedures should be followed for CAR T candidates who have come into close contact with infected individuals, with CAR T-cell therapy should be delayed for the 14-day period. Any patients who develop COVID-19 during their hospitalization for CAR T-cell therapy administration should be managed according to their present symptoms and most recent treatment guidelines.
How can CAR T-cell patients at risk for COVID-19 best be supported and managed?
Managing COVID-19 risk prior to CAR T-cell therapy involves appropriate screening measures and testing at the relevant time points (including before apheresis, before lymphodepleting chemotherapy, and before and after CAR T-cell infusion) and preventative measures such as telemedicine and personal protective equipment, like face masks.
为了支持患者患者T-Cell治疗，医生应与护理人员合作，限制接入的人，同时通过远程医疗保持密切监测。后汽车T细胞疗法支持治疗应按照护理标准调整，包括感染预防和符合Covid-19建议。
More detailed recommendations of pre- and post-CAR T-cell therapy can be foundhere。
Conclusion
对于需要的患者，延迟汽车T细胞治疗将是有害的，除非通过Covid-19感染或更高的毒性风险或差的结果。通过定期更新的准则，适应反映最相关的信息，应安全地继续为患者和医生安全地继续。Covance致力于从这些专家建议中学到学习，并在汽车T细胞领域的持续临床研究活动中实施它们。
References:
- Bachanova V, Bishop MR, Dahi P, Dholaria B, Grupp SA, Hayes-Lattin B, Janakiram M, Maziarz RT, McGuirk JP, Nastoupil LJ, Oluwole OO, Perales MA, Porter DL, Riedell PA; CAR T-cell Consortium. Chimeric Antigen Receptor T Cell Therapy During the COVID-19 Pandemic. Biol Blood Marrow Transplant. 2020 Jul;26(7):1239-1246.
